Stimulant Medications for ADHD in Autism Spectrum Disorder

Recruiting at 11 trial locations

Overseen By Aria Dockham, MACPR

Age: < 18

Sex: Any

Trial Phase: Phase 4

Sponsor: Daniel Coury

Must not be taking: ADHD medications

Disqualifiers: Unstable medications, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

500 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is a pragmatic clinical trial examining the comparative effectiveness of two stimulant medications (methylphenidate and amphetamine) in the treatment of ADHD in children and adolescents with autism. Using a sequential, multiple assignment randomization trial (SMART) design the study will not only assess these two medications but also the role of an increasingly popular class of ADHD medication, the alpha-2 agonists. Findings from this study will help improve clinicians' approach to medication selection and reduce the repeated trials of multiple medications that are current standard care.

Will I have to stop taking my current medications?

You may need to stop taking your current ADHD medications at least 7 days before joining the trial. However, you can continue taking other medications like SSRIs, atypical antipsychotics, or anticonvulsants if your dose has been stable for more than 4 weeks.

Is it safe to use stimulant medications for ADHD in individuals with Autism Spectrum Disorder?

Research shows that alpha-2 adrenergic agonists like guanfacine and clonidine, as well as stimulants like methylphenidate and amphetamines, are generally safe for treating ADHD in children and adolescents. Common side effects include sedation, fatigue, and mild reductions in heart rate and blood pressure, but these rarely lead to stopping treatment. Newer formulations have improved tolerability and effectiveness. ^{1 2 3 4 5}

How is the drug treatment for ADHD in Autism Spectrum Disorder unique?

This treatment is unique because it combines stimulant medications like amphetamines and methylphenidate with alpha-2 agonists such as guanfacine and clonidine, which may offer a broader approach to managing ADHD symptoms in individuals with autism. The inclusion of alpha-2 agonists, which have a different mechanism of action by targeting specific receptors in the brain, may help address the complex needs of patients with both ADHD and autism. ^{3 6 7 8 9}

Research Team

Daniel Coury, MD

Principal Investigator

Nationwide Children's Hospital

Karen Kuhlthau, PhD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

This trial is for children and adolescents aged 4-17 with both Autism Spectrum Disorder (ASD) and ADHD. They must be able to take medication, have a consistent caregiver, and can be on stable doses of other psychotropic meds. Excluded are those who've had multiple ADHD med trials within the last year or any safety risks.

Inclusion Criteria

Patient and/or legally authorized representative must be willing and able to give informed consent/assent for participation in this study

I have been on a stable dose of my mental health medication for over 4 weeks.

Patient and their caregiver must be willing and able (in the Investigator's opinion) to comply with all study requirements

Exclusion Criteria

I have tried more than one ADHD medication in the last year.

I have no health issues that would make it unsafe for me to take the study medications.

Less than 4 weeks since last ADHD medication was taken

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Stage 1 Treatment

Randomization to either Amphetamine (AMP) or Methylphenidate (MPH) based on discussion between physician and parent/caregiver

8 weeks

Bi-weekly virtual assessments

Stage 2 Treatment

Randomization to either Alpha-2 Agonist or alternate stimulant not used in Stage 1

8 weeks

Bi-weekly virtual assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Alpha 2 agonist
• Amphetamine
• Methylphenidate

Trial Overview The study tests two stimulant medications—methylphenidate and amphetamine—for treating ADHD in kids with autism. It also examines alpha-2 agonists' effectiveness using a SMART design to potentially streamline medication selection for this group.

Participant Groups

Group I: Stage 1 - Stimulant Active Control 1 Intervention

This proposed naturalistic, pragmatic clinical trial does not involve investigational drugs. Sequential, multiple assignment randomized trial (SMART) pragmatic clinical trial. Stage 1 - randomization to either Amphetamine (AMP) or Methylphenidate (MPH). The specific medication prescribed by the physician will be determined by discussion between physician and parent / caregiver and review of the subject's insurance coverage. Subjects will receive their medication from their pharmacy.

Group II: Stage 2 - Alpha-2 Agonist or Alternate Stimulant Active Control 1 Intervention

Stage 2 - randomization to either Alpha-2 Agonist or other stimulant not randomized to in Stage 1: Amphetamine (AMP) or Methylphenidate (MPH). (frequency, dosage, format, and duration dependent on participant and study doctor discussion).

Alpha 2 agonist is already approved in United States, European Union for the following indications:

Approved in United States as Guanfacine for:

• Attention Deficit Hyperactivity Disorder (ADHD)
• Hypertension

Approved in United States as Clonidine for:

• Attention Deficit Hyperactivity Disorder (ADHD)
• Hypertension

Approved in European Union as Guanfacine for:

• Attention Deficit Hyperactivity Disorder (ADHD)

Approved in European Union as Clonidine for:

• Hypertension

Who Is Running the Clinical Trial?

Daniel Coury

Lead Sponsor

Trials

1

Recruited

500+

MaineHealth

Collaborator

Trials

76

Recruited

43,800+

University of Alberta

Collaborator

Trials

957

Recruited

437,000+

University of Michigan

Collaborator

Trials

1,891

Recruited

6,458,000+

University of Virginia

Collaborator

Trials

802

Recruited

1,342,000+

Massachusetts General Hospital

Collaborator

Trials

3,066

Recruited

13,430,000+

University of Rochester

Collaborator

Trials

883

Recruited

555,000+

Patient-Centered Outcomes Research Institute

Collaborator

Trials

592

Recruited

27,110,000+

University of California, Irvine

Collaborator

Trials

580

Recruited

4,943,000+

Holland Bloorview Kids Rehabilitation Hospital

Collaborator

Trials

69

Recruited

14,100+

Findings from Research

In a 2-year open-label study involving participants aged 6-17 with ADHD, extended-release guanfacine (GXR) demonstrated long-term safety and efficacy, with most adverse events being mild to moderate.

Significant improvements in ADHD symptoms were observed as early as the first month and continued throughout the 24-month treatment period, supporting GXR as a viable monotherapy for ADHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term safety and efficacy of guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder. Sallee, FR., Lyne, A., Wigal, T., et al.[2013]

Alpha(2)-agonists like guanfacine and clonidine, originally developed for hypertension, have been effectively used for nearly 30 years to treat conditions such as ADHD and Tourette's syndrome, showing improvements in hyperactivity and inattention in children.

Guanfacine selectively targets alpha(2A)-receptors, which may enhance prefrontal function, and while both medications can cause sedation and fatigue, their effects on heart rate and blood pressure are generally modest and do not often lead to treatment discontinuation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alpha-2 adrenergic agonists in children with inattention, hyperactivity and impulsiveness. Scahill, L.[2021]

Recent research has led to the approval of several long-acting medications for pediatric ADHD, including dexmethylphenidate XR, lisdexamfetamine, and the methylphenidate transdermal system, all showing efficacy similar to traditional treatments but with extended duration of action (up to 13 hours).

Atomoxetine, the first non-stimulant ADHD treatment, has a slower onset of effect (2-8 weeks) and is less effective than stimulants, but it can benefit some children who do not respond to traditional medications, highlighting the need for diverse treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Attention-deficit hyperactivity disorder: recent advances in paediatric pharmacotherapy. May, DE., Kratochvil, CJ.[2021]

Combining psychostimulants with new controlled-release formulations of alpha2-adrenergic agonists, like guanfacine and clonidine, can significantly enhance treatment efficacy for ADHD in children and adolescents without compromising safety.

These new formulations address previous limitations of rapid absorption and side effects, making them a promising option for patients with complex ADHD who may not respond well to monotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of alpha2-adrenergic agonists in attention-deficit/hyperactivity disorder. Sallee, FR.[2022]

In a study of 497 preschool-aged children treated for ADHD, α-2 adrenergic agonists (A2A) were associated with more daytime sleepiness and headaches, while stimulants led to higher rates of moodiness, sleep difficulties, and appetite suppression.

Overall, stimulants had a greater frequency of adverse effects compared to A2A medications, suggesting that the choice of treatment should consider both efficacy and the distinct side effect profiles of these medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Effects of α-2 Adrenergic Agonists and Stimulants in Preschool-age Attention-deficit/Hyperactivity Disorder: A Developmental-Behavioral Pediatrics Research Network Study. Loe, IM., Blum, NJ., Shults, J., et al.[2023]

A study involving 226 children (174 retrospectively and 52 prospectively) found that stimulant medications like methylphenidate significantly improved symptoms of hyperactivity, impulsivity, and inattention in children with autism spectrum disorders (ASD) and ADHD, without worsening tics or repetitive behaviors.

The side effects were generally mild, with children in the ADHD-only group experiencing more nausea and headaches, while only sleep difficulties were noted in the ASD group, suggesting that stimulants can be safely used in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of comorbid autism spectrum disorders on stimulant response in children with attention deficit hyperactivity disorder: a retrospective and prospective effectiveness study. Santosh, PJ., Baird, G., Pityaratstian, N., et al.[2013]

Methylphenidate and atomoxetine, common treatments for ADHD, can also help reduce symptoms in patients with both ADHD and autism spectrum disorders (ASD), but their effectiveness may be lower in those with ASD.

Patients with ASD may experience poorer tolerance to these medications due to the complexity of their condition, indicating a need for further controlled studies to better understand the long-term safety and efficacy of these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Autism and attention deficit hyperactivity disorder: pharmacological intervention]. Fernández-Jaén, A., Martín Fernández-Mayoralas, D., Fernández-Perrone, AL., et al.[2015]

Currently, the main treatments for ADHD are stimulant medications like methylphenidate and the non-stimulant atomoxetine, but there is no approved medication specifically for adults with ADHD.

Newer treatments in development, such as SPD-503 and various glutamatergic receptor agonists, aim to provide alternative mechanisms of action, potentially addressing limitations of existing therapies, including concerns about stimulant abuse and side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Stimulant and non-stimulant medication in current and future therapy for ADHD]. Franke, AG., Konrad, A., Lieb, K., et al.[2018]

A review of 11 studies, including 4 randomized controlled trials, suggests that psychostimulants, particularly methylphenidate, may effectively reduce ADHD-like symptoms in individuals with autism spectrum disorder.

Common side effects of psychostimulants include reduced appetite, sleep difficulties, irritability, and emotional outbursts, highlighting the need for careful monitoring and tailored treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Psychostimulants for ADHD-like symptoms in individuals with autism spectrum disorders. Cortese, S., Castelnau, P., Morcillo, C., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Long-term safety and efficacy of guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder. [2013]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Alpha-2 adrenergic agonists in children with inattention, hyperactivity and impulsiveness. [2021]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Attention-deficit hyperactivity disorder: recent advances in paediatric pharmacotherapy. [2021]

4. England pubmed.ncbi.nlm.nih.gov

The role of alpha2-adrenergic agonists in attention-deficit/hyperactivity disorder. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Adverse Effects of α-2 Adrenergic Agonists and Stimulants in Preschool-age Attention-deficit/Hyperactivity Disorder: A Developmental-Behavioral Pediatrics Research Network Study. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Impact of comorbid autism spectrum disorders on stimulant response in children with attention deficit hyperactivity disorder: a retrospective and prospective effectiveness study. [2013]

7. Spain pubmed.ncbi.nlm.nih.gov

[Autism and attention deficit hyperactivity disorder: pharmacological intervention]. [2015]

8. Germany pubmed.ncbi.nlm.nih.gov

[Stimulant and non-stimulant medication in current and future therapy for ADHD]. [2018]

9. England pubmed.ncbi.nlm.nih.gov

Psychostimulants for ADHD-like symptoms in individuals with autism spectrum disorders. [2022]